ISHL10 Abstract T005

High expression of programmed cell death receptor 1 (PD-1) in the tumor microenvironment is associated with inferior event free survival in classical Hodgkin Lymphoma

Immune checkpoint inhibition targeting the programmed cell death receptor 1 (PD-1) pathway is a novel treatment approach in relapsed and refractory classical Hodgkin lymphoma (cHL). Use of PD1-inhibitors may be justified early on in selected patients if patients with high risk of treatment failure could be identified at the time of diagnosis. Our aim was to investigate the prognostic impact of PD-1 expression in tumor infiltrating lymphocytes in diagnostic cHL biopsies. Patients from Aarhus, Denmark (n=283) diagnosed 1990-2006 aged 15-86, and Sweden (n=132) diagnosed 1999-2002 aged 18-74 were included. The patients were mostly treated with chemotherapy (mainly ABVD) ± radiotherapy. Tissue microarray samples were available from 387 patients. Immunohistochemistry was used to detect PD-1 and the percentage of positive cells was estimated using a digital image analysis program. Fifty-seven patients (15%) presented with a high expression of PD-1, defined as ≥10% positive lymphocytes in the tumor microenvironment. Overall survival (OS) and event free survival (EFS) (treatment failure or death from any cause) were analyzed using log rank test and Cox proportional hazards regression. The median follow-up time was 10.8 years. Among patients with a high expression of PD-1 there were 29 (51%) events, and among those with a low expression 104 (32%)(Figure 1). A high PD-1 expression was associated with an inferior EFS (age-adjusted hazard ratio (HR)=1.69; 95% confidence interval (95%CI) 1.12-2.54), an observation which persisted also in a fully adjusted analysis (adjusted for age, albumin <40g/L, B-symptoms, bulky tumor, country, extranodal tumor involvement, sex, stage IIB-IV, and white blood cell count >15x109/L) (HR=1.80; 95%CI 1.19-2.90). High PD-1 was not significantly associated with worse OS. There was a weak correlation between high expression of PD-1 and intratumoral Epstein-Barr virus negativity (Spearman correlation coefficient 0.12, p=0.015), and nodular sclerosis histologic subtype (correlation coefficient 0.10, p=0.04). This is the first study to show that high expression of PD-1 in the tumor microenvironment of cHL is associated with inferior EFS (fully adjusted multivariate analyses). Patients with high expression of PD-1 have a tumor permissive exhausted immune system and may therefore be more likely to experience treatment failure after conventional treatment regimens.